Synthesis of Acyclic and Allylic Epoxy Alcohols
A R T I C L E S
and allylic epoxy alcohols with three contiguous stereocenters
from prochiral starting materials in good to excellent yields
(Table 2). This one-pot two-step protocol begins with a highly
enantioselective C-C bond-forming reaction to install the initial
chiral center of the allylic alkoxide (Schemes 2 and 3). In the
second step, the resulting allylic alkoxide is then diastereose-
lectively epoxidized in situ in the presence of a zinc peroxide
species and a titanium tetra-alkoxide.
Our approach employs several different methods for the first
step in our one-pot procedure, the synthesis of the allylic
alkoxide intermediate (Scheme 2, Routes A and B). The first
of these is alkyl addition to enals promoted by one of three
different ligand systems: two different bis(sulfonamide) ligands
tetraalkoxide. The first route to generation of the zinc peroxide
species is by insertion of dioxygen into a zinc-alkyl bond
30-39
(
Scheme 4).
We have previously demonstrated that this zinc
i
t
peroxide, in the presence of Ti(O Pr)4 or Ti(O Bu)4, will
epoxidize the allylic alkoxide intermediate.
20,21,40
Intramolecular
oxygen atom transfer from the peroxide to the allylic alkoxide
and hydrolysis of the reaction mixture, affords the epoxy alcohol
(
(
Scheme 2, Route A, L*1, and L*2) and Nugent’s (-)-MIB
4
0
product. Due to the practical difficulties associated with
controlling the rate of delivery of dioxygen to reaction mixtures
containing dialkylzinc reagents, an alternative route to the
formation of a zinc peroxide was explored. TBHP is a
commercially available stoichiometric oxidant that is commonly
used in the transition-metal catalyzed epoxidations of allylic
L*3).22 To demonstrate the ability of different catalyst systems
to facilitate the initial C-C bond-forming reaction, various alkyl
zincs were added to aldehydes asymmetrically in the presence
of either MIB (Table 2, column 1) or one of 2 bis(sulfonamide)
ligands (Table 2, column 2).2
3-26
Both catalyst systems have
previously been shown to exibit good enantioselectivities and
1
alcohols. In our system, TBHP would protonate an ethyl group
yields for diethylzinc additions to aldehydes.2
3,27
The reaction
on the organozinc reagent to yield ethane and an alkyl zinc tert-
butyl peroxide species (Scheme 4).
times decreased from over 24 h for the amino alcohol ligand,
MIB, to under 2 h with the bis(sulfonamide) ligands, L*1 and
L*2. Both of the catalyst systems promoted the reaction with
enantioselectivities >90%. (Table 2, entries 1-8).
When MIB was used as the ligand, in the asymmetric
addition/diastereoselective epoxidation, a catalytic amount of
titanium tetraisopropoxide was added (20 mol %) after the
generation of the zinc peroxide species at -20 °C. In the case
of the titanium bis(sulfonamide)-based catalysts, the reaction
mixture was simply cooled to -20 °C and exposed to the
oxidant, TBHP or dioxygen.
The results of the asymmetric addition/diastereoselective
epoxidation are shown in Table 2. Entries 1-11 have been
synthesized via dialkylzinc additions to enals. The remaining
entries were generated from vinylzinc addition to simple
aldehydes. For the most part, the diastereoselectivities and yields
are similar, regardless of whether the epoxidation step is carried
out in the presence of dioxygen or TBHP. (Compare columns
It is known that the rate of dimethylzinc addition to enals
with MIB and related amino alcohol ligands is slow; therefore,
we were unable to achieve satisfactory yields of the methyl
28
addition products, even after 2 days at room temperature. The
t
bis(sulfonamide) ligand L*2 and Ti(O Bu)4 were employed in
this reaction, because the resulting catalyst is known to promote
dimethylzinc additions to aldehydes with high levels of enan-
tioselectivity (Table 2, entries 9-11).2 In our reaction system,
4,29
t
4
mol % of ligand L*2 and 1.2 equiv of Ti(O Bu)4 were utilized
to successfully promote the addition of dimethylzinc to enals.
Another route to generation of allylic alkoxide intermediates
is via synthesis and isolation of a divinylzinc species and
subsequent addition to a simple aldehyde (Scheme 2, Route B).
The trisubstituted, tetrasubstituted, or R-methyl vinylzinc species
are all generated by exposing the corresponding vinyl bromide
to lithium metal and zinc bromide. After sonication of the
reaction mixture in diethyl ether at 0 °C under an argon
atmosphere, the substituted divinylzinc is isolated and purified
by sublimation. Vinyl additions to aldehydes in the presence
of MIB or the titanium bis(sulfonamide) catalyst L*1 typically
lead to allylic alcohols with ee’s >90% (Table 2, entries 12
and 13).
1
and 2 of Table 2 with column 3.) The yields tended to be
slightly higher in the reactions with TBHP, as the crude epoxy
alcohols generated were cleaner. The stereochemistry of the
41
product in entry 4 was confirmed by X-ray crystallography.
Our system is unique in that it demonstrates high levels of
diastereoselectivity in the epoxidation step for substrates that
1,2
1,3
exhibit either A or A strain in one of their diastereomeric
transition states. Other known substrate-directed epoxidation
methods tend to show high diastereoselectivity for one type of
15
substrate, but not the other, as illustrated in Table 1. We
suspect that our titanium allylic alkoxide/zinc peroxide species
has a different set of diastereomeric transition states from the
The second step of our one-pot approach consists of a diaster-
eoselective epoxidation of the allylic zinc alkoxide intermediate
in the presence of a zinc peroxide species and a titanium
(30) Seyferth, D. Organometallics 2001, 20, 2940-2955.
(
31) Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215-1225.
32) Lewinski, J.; Ochal, Z.; Bojarski, E.; Tratkiewicz, E.; Justyniak, I.;
Lipkowski, J. Angew. Chem., Int. Ed. 2003, 42, 4643-4646.
(
(
22) Nugent, W. A. Chem. Commun. 1999, 1369-1370.
23) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem.
Soc. 1998, 120, 6423-6424.
(
(33) Lewinski, J.; Marciniak, W.; Lipkowski, J.; Justyniak, I. J. Am. Chem. Soc.
2003, 125, 12698-12699.
(
(
(
24) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
(34) Enders, D.; Ahu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35,
1725-1728.
Tetrahedron 1992, 48, 5691-5700.
25) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M.
Tetrahedron Lett. 1989, 30, 7095-7098.
(35) Enders, D.; Kramps, L.; Zhu, J. Tetrahedron: Asymmetry 1998, 9, 3959-
3962.
26) Prichett, S.; Woodmanee, D.; Davis, T.; Walsh, P. J. Tetrahedron Lett.
(36) Yu, H.-B.; Zheng, X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-S.; Pu, L. J.
Org. Chem. 1999, 64, 8149-8155.
1
998, 39, 5941-5942.
(
(
27) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(37) van der Deen, H.; Kellogg, R. M.; Feringa, B. L. Org. Lett. 2000, 2, 1593-
28) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
1595.
1
11, 4028-4036.
(38) Yamamoto, K.; Yamamoto, N. Chem. Lett. 1989, 1149-1152.
(39) Enders, D.; Zhu, J. Q.; Kramps, L. Liebigs Ann. Chem. 1997, 1101-1113.
(40) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-9545.
(
29) Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett. 1994, 35, 4539-
4
540.
J. AM. CHEM. SOC.
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